- Mac (voiced by Sean Marquette) – A bright, and imaginative eight-year-old boy who is Bloo's creator and the protagonist of the series. Mac visits Foster's every day. He is very attached to Bloo and his biggest fear is never seeing him again. Mac is often the voice of reason among his friends when they are making decisions. Mac becomes extremely high and hyperactive when he eats sugar. He also has a crush on Frankie.
- Bloo (voiced by Keith Ferguson) – Mac's pet and best friend. He is blue-colored and resembles a simple, domed cylinder. Bloo is often very self-centered, egotistic and narcissistic, as well as having a knack for getting in trouble. Despite all this, he still has a good heart and apologizes for his wrongdoings. Bloo loves paddle balls, even though he typically cannot make the ball hit the paddle.
- Wilt (voiced by Phil LaMarr) – A very tall, friendly and incredibly nice red-colored friend with only a right arm and a crooked left eye-stalk. His overtly passive demeanor is often taken advantage of by the other imaginary friends. He is a basketball player and fan, and is the former imaginary friend of Jordan Michaels (a parody of Michael Jordan). After an accident during a basketball game, Wilt left Jordan, fearing the latter would be disappointed by Wilt's losing the game. Years later, Wilt goes on a search to re-encounter Jordan.
- Eduardo (voiced by Tom Kenny) – A Latin American monster created by a young girl, Nina Valerosa, to protect her in a dangerous neighborhood. Eduardo is big, hairy and violet-purple sloth who has horns, a snout, a pointy demon-like tail and large teeth. Despite his large size, overwhelming strength, and menacing appearance, Eduardo is docile, timid and scared of almost anything. However, he can be ferocious if angered or when danger befalls his friends.
- Coco (voiced by Candi Milo) – A bird with palm tree-like hair who can only say or write her name. A talent unique to her is her ability to lay colorful, plastic eggs containing a plethora of objects, at will. Other characters usually understand her when she speaks. Despite her appearance and quirky behavior, she can demonstrate intelligence and kindness. Her creator is unknown, as she was found on a South Pacific island by two scientists named Adam and Douglas.
- Frankie Foster (voiced by Grey DeLisle) – Madame Foster's redheaded granddaughter, addressed as "Miss Frances" by Mr. Herriman. Frankie is the caregiver at Foster's and helps keep everything in order. She is usually very friendly, capable, easygoing, hard-working, thoughtful, caring, and sweet, but occasionally loses her patience with Bloo and Mr. Herriman. According to her driver's license, she was born on July 25, 1984.
- Mr. Herriman (voiced by Tom Kane) – A gray and white elderly anthropomorphic lop ear rabbit friend imagined by Madame Foster who speaks with a British accent. He wears a tailcoat, white gloves, a top hat and a monocle. He presents himself as head of business affairs of the house and later as President of the house, and is extremely strict about rules and the maintenance of order in the home. He frequently punishes Bloo for his various misdemeanors and scolds Frankie for her perceived laziness, despite all her hard work.
- Madame Foster (voiced by Candi Milo) – The caring founder of Foster's and grandmother of Frankie. She is the creator of Mr. Herriman. Despite being elderly, Madame Foster has childlike boundless energy and occasionally becomes hyperactive and mischievous.
- Terrence (voiced by Tara Strong) Mac's thirteen-year-old brother and the recurring villain of the series. He enjoys bullying Mac and coming up with various schemes to make Mac's life hard and miserable, usually trying to keep Mac and Bloo from seeing each other ever again. His stupidity always gets the better of him, making him easily outsmarted by Mac or Bloo.
- Duchess (voiced by Grey DeLisle) A "high-maintenance" pedigree friend who is pompous, ugly, rude, arrogant, selfish, self-centered, and lazy up to the points she orders Frankie to open her eyelids for her first thing in the morning. She considers herself superior to all the other imaginary friends, is extremely negative towards everyone, and never says anything nice (despite this, she has helped someone in four episodes, albeit for selfish reasons). Whenever Duchess turns on the spot, her entire body pivots like a sheet of paper being flipped, revealing that she is two-dimensional (however, in the pilot movie "House of Bloo's", she was not two-dimensional). Her full name is "Her Royal Duchess Diamond Persnickety the First, Last, and Only". She speaks with a German accent.
- Cheese (voiced by Candi Milo) A simple, pale-yellow-colored friend who debuted in "Mac Daddy". Cheese was thought to be an imaginary friend accidentally created by Mac, but was actually created by Mac's neighbor Louise. He appears to be a nuisance and dim-witted, often saying incoherent or non-sequitur phrases, and breaking into sudden bouts of screaming when frightened or when he doesn't get his way. Cheese likes goldfish crackers, cereal, juice, chocolate milk (although he is lactose-intolerant), etc. In the series finale "Goodbye to Bloo", he becomes the newest resident at Foster's, much to the other residents' horror.
- Goo (voiced by Grey DeLisle) A hyper-imaginative, talkative girl who first appeared in the episode "Go Goo Go". Her parents allowed her to name herself when she was a baby resulting in the full name "Goo Goo Ga Ga". Goo enjoys playing games such as Checkers and Truth or Dare, but she does not know how to play and Mac is the only one who notices. In her first appearance she constantly created friends because she had no real friends because of her odd behavior. She finally stopped making new friends and undoes them after Mac told her to get to know the ones she had made already. However, she has still created a few by mistake or to help on rare occasions. She is also shown to be friends with Cheese, as both of them get along because of their odd doings. She looks a little older than Mac, though it's never been stated how old she is
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